LINE-1 Evasion of Epigenetic Repression in Humans Sánchez Luque, Francisco José García Cañadas, Marta Muñoz López, Martin Rodríguez Heras, Sara García Pérez, José Luis Epigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells. However, the mechanisms that repress young L1 families and how L1 escapes to cause somatic genome mosaicism in the brain remain unclear. Here we report that a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation in pluripotent and differentiated cells. By analyzing 24 hippocampal neurons with three distinct singlecell genomic approaches, we characterized and validated a somatic L1 insertion bearing a 3ʹ transduction. The source (donor) L1 for this insertion was slightly 5ʹ truncated, lacked the YY1 binding site, and was highly mobile when tested in vitro. Locusspecific bisulfite sequencing revealed that the donor L1 and other young L1s with mutated YY1 binding sites were hypomethylated in embryonic stem cells, during neurodifferentiation, and in liver and brain tissue. These results explain how L1 can evade repression and retrotranspose in the human body. 2024-02-07T11:58:18Z 2024-02-07T11:58:18Z 2019 info:eu-repo/semantics/article Sanchez-Luque FJ, Kempen MHC, Gerdes P, Vargas-Landin DB, Richardson SR, Troskie RL, Jesuadian JS, Cheetham SW, Carreira PE, Salvador-Palomeque C, García-Cañadas M, Muñoz-Lopez M, Sanchez L, Lundberg M, Macia A, Heras SR, Brennan PM, Lister R, Garcia-Perez JL, Ewing AD, Faulkner GJ. LINE-1 Evasion of Epigenetic Repression in Humans. Mol Cell. 2019 Aug 8;75(3):590-604.e12. doi: 10.1016/j.molcel.2019.05.024. Epub 2019 Jun 20. PMID: 31230816. https://hdl.handle.net/10481/88588 10.1016/j.molcel.2019.05.024 eng eu-repo/grantAgreement/EC/FP7/623324; eu-repo/grantAgreement/EC/FP7/309433 http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier